CN104987323A - Preparation method of Dabigatran etexilate - Google Patents
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Abstract
The invention relates to a preparation method of Dabigatran etexilate. In a preparation process, acyl chloride or anhydride is used for replacing N, N minute-Carbonyldiimidazole (CDI ) or palladium on activated carbon, which must be used and is expensive in the prior art, the cost is greatly lowered, and used materials are cheap and are easily available, the process is simple and feasible, aftertreatment steps are simplified, column chromatography purification is not needed in whole operation steps, so that the process of the whole preparation method is simplified, and industrialization is convenient to realize; when a compound with a formula 2 is compounded, a sodium amide and ammonium salt system is adopted, and generation of a mass of acid pickle is avoided, so the production is safe, the environment is not polluted, and the preparation process is convenient and easy; when a compound with a formula 1 is compounded, a stable-property compound with a formula 7 is adopted, great convenience is brought for production, and the yield of the Dabigatran etexilate is effectively improved; the total yield of the Dabigatran etexilate prepared by the method reaches 60 to 70 percent.
Description
Technical field
The present invention relates to the synthesis technical field of compound, specifically refer to a kind of preparation method of dabigatran etcxilate.
Background technology
Dabigatran etcxilate (English name: Dabigatran etexilate) chemistry 3-by name [[[2-[[[4-[[[(hexyloxy) carbonyl] is amino] formamino] phenyl] is amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-base] carbonyl] (pyridine-2-base) is amino] ethyl propionate, structural formula is
It is a kind of direct thrombin inhibitor of novel synthesis, is the prodrug of dabigatran, belongs to the thrombin inhibitors of non-peptide class.Dabigatran etcxilate is developed by German Boehringer Ingelheim company, takes the lead in going on the market in April, 2008 in Germany and Britain, and within 2010, in U.S.'s listing, in March, 2013 by CFDA import authentication registration, and went on the market at home in 2013.This is the first new classification oral anticoagulant thing gone on the market over 50 years after warfarin, at present in 80 the national list marketings in the whole world.
Dabigatran etcxilate is oral after gastrointestinal absorption, can be converted into the dabigatran with direct anticoagulant active in vivo.Dabigatran is incorporated into the scleroproein specific binding site of zymoplasm, stops Fibrinogen to be cracked into scleroproein, thus has blocked final step and the thrombosis of blood coagulation waterfall network.The listing of dabigatran etcxilate is a major progress in anticoagulation therapy field and potential lethality thrombus prevention field, has milestone significance.The progress that dabigatran etcxilate substitutes warfarin is quickish, and market estimates that dabigatran etcxilate has the potentiality becoming cookle, estimates that the highest sales revenue will reach about 9,000,000,000 dollars, is of great immediate significance to the exploitation of dabigatran project.
The synthetic route of current published dabigatran etcxilate has following several:
Route 1:
As shown in Figure 4, this route first time is reported in patent WO09837075A.Wherein, formula I and formula II compound act on ShiShimonoseki ring at N, N '-carbonyl dimidazoles (CDI) and generate formula III compound, and formula III compound reacts production IV compound with volatile salt again under acid effect.This synthetic method yield is very low, and total recovery is only 36.6%, and can produce a large amount of spent acid solution in building-up process, causes larger environmental pollution, thus limits the suitability for industrialized production of dabigatran etcxilate; Meanwhile, employ the unstable just own ester of chloroformic acid when synthesis type VI compound, this can bring certain potentially dangerous to production operation.
Route 2:
As shown in Figure 5, this route is announced by patent WO2011061080A, and the key intermediate 2 in this route needs to use cyclization reagent 5 in preparation process, and cyclization reagent 5 is Mono Chloro Acetic Acid, chloroacetyl chloride, sym-dichloroacetic anhydride or triethoxy monochloroethane.When using Mono Chloro Acetic Acid, yield is extremely low; Use during chloroacetyl chloride cyclization and easily produce two acidylate impurity, yield is low, only has 70%; Sym-dichloroacetic anhydride is expensive, adds production cost largely; And the non-commercialization of triethoxy monochloroethane, need self-control, cause whole building-up process complicated, also correspondingly add preparation cost.
Route 3:
As shown in Figure 6, this route was disclosed in 2006 by patent application WO2007071743A, and total recovery is not high.After 1 and 2 reactions obtained 3, need to separate 3 then to carry out hydrogenation, and the impurity of two benzoxazoles ring can be produced in the condensation process, must by the not only time-consuming but also heat filtering of requiring great effort removing, not only cause whole preparation process complicated, also fall the total recovery of preparation process; And the condensation reagents such as carbonyl dimidazoles, pivaloyl chloride, propane phosphoric anhydride will be used in the process preparing benzoxazoles ring, wherein carbonyl dimidazoles and propane phosphoric anhydride expensive, be all not suitable for suitability for industrialized production.
Route 4:
As shown in Figure 7; this route is announced in 2013.03.28 by patent WO2013144903A1; compared with route 1; the step that cyano group acidylate becomes acid amides to obtain compound 1 to become to narrow again by this route many steps after acidylate closed loop; this synthetic route is as broad as long in route 1 in itself, and adds a step that yield may be caused to decline.
Therefore, for the preparation method of current dabigatran etcxilate, await doing further improvement.
Summary of the invention
Technical problem to be solved by this invention is the present situation for prior art, the preparation method of the dabigatran etcxilate that a kind of yield is high, cost is low is provided, the method processing step is simple, use raw material to be cheaply easy to get, be convenient to realize industrialization, and unharmful substance produces in whole preparation process, production safety, environmentally safe.
The present invention solves the problems of the technologies described above adopted technical scheme: a kind of preparation method of dabigatran etcxilate, it is characterized in that comprising the following steps:
(1) make following formula 6 compound and containing oxygen derivative react and generate following formula 5 compound, formula 5 compound reacts with following formula 4 compound and generates acid amides, underpressure distillation is except to be dissolved in by resistates after desolventizing in organic solvent and to react 3 ~ 5h at 75 ~ 95 DEG C, wash after completion of the reaction and concentrate organic phase, filtration, drying obtain following formula 3 compound;
Wherein, X is carbon or sulphur, and Y is the alkyl or the alkoxyl group that contain 1 ~ 10 carbon atom;
(2) formula 3 compound and sodium amide is made to be obtained by reacting following formula 2 compound;
(3) be dissolved in solvent by following formula 2 compound, and at 0 ~-5 DEG C, instill the reaction of following formula 7 compound, obtain following formula 1 compound after completion of the reaction, formula 1 compound is described Dabigatran compound.
In such scheme, formula 3 compound described in step (2) and sodium amide react in the mixed solvent of ethanol and methylene dichloride, and temperature of reaction is 20 ~ 25 DEG C.
As improvement, formula 3 compound and sodium amide described in step (2) react after solvent is removed in complete underpressure distillation and add in ammonium salt aqueous solution, and at 0 ~ 10 DEG C, filtration after stirring 2 ~ 3h, drying, obtain described formula 2 compound.
In above-mentioned each preferred version, described in step (1), the mol ratio of formula 6 compound and formula 4 compound is 1 ~ 2: 1.Described in step (3), the mol ratio of formula 2 compound and formula 7 compound is 1 ~ 2: 1.
Preferably, the solvent described in step (3) is the mixed solution of acetone and water, and the volume ratio of described acetone and water is 0.5 ~ 2: 1.
As preferably, the containing oxygen derivative described in step (1) is the one in acyl chlorides, acid anhydrides, tert-Butyl dicarbonate, chloro-formic ester.
Preferably, the organic solvent described in step (1) be in tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, acetonitrile, methylene dichloride, trichloromethane, ethyl acetate, isopropyl acetate, butylacetate any one or multiple.
Preferably, described ammonium salt is volatile salt or ammonium chloride.
Compared with prior art, the invention has the advantages that:
(1) in preparation process of the present invention, replace must using and expensive N in prior art with acyl chlorides or acid anhydrides, N '-carbonyl dimidazoles (CDI) or palladium carbon, greatly reduce cost, and the raw material used cheaply be easy to get, simple for process, simplify post-processing step, without the need to using purification by column chromatography in whole operation steps, make whole preparation method's work simplification, be convenient to realize industrialization;
(2) the present invention is in synthesis type 2 compound, adopts sodium amide and ammonium salt system, avoids the generation of a large amount of spent acid solution, not only production safety, environmentally safe, also make preparation process simple and easy to do;
(3) when synthesis type 1 compound, have employed formula 7 compound of stable in properties, bring great convenience to production, and effectively improve the yield of dabigatran etcxilate, the total recovery that the present invention prepares dabigatran etcxilate reaches 60 ~ 70%.
Accompanying drawing explanation
Fig. 1 is the ESI-MS mass spectrum of the embodiment of the present invention 1 Chinese style 3 compound;
Fig. 2 is the ESI-MS mass spectrum of the embodiment of the present invention 1 Chinese style 2 compound;
Fig. 3 is the ESI-MS mass spectrum of the embodiment of the present invention 1 Chinese style 1 compound;
Fig. 4 is the step schematic diagram of synthetic route 1 in background technology;
Fig. 5 is the step schematic diagram of synthetic route 2 in background technology;
Fig. 6 is the step schematic diagram of synthetic route 3 in background technology;
Fig. 7 is the step schematic diagram of synthetic route 4 in background technology.
Embodiment
Below in conjunction with accompanying drawing embodiment, the present invention is described in further detail.
Embodiment 1:
In the present embodiment, the preparation method of dabigatran etcxilate comprises the following steps:
(1), under room temperature, by 100g formula 6 compound, the mixing of 1000mL THF, 120mL triethylamine, be cooled to 0 DEG C, add 85mL pivaloyl chloride and insulation reaction 0.5h in less than 10 DEG C; Add 204g formula 4 compound after completion of the reaction, at 45 DEG C, react 2h; Add in 2000mL n-butyl acetate by organic layer evaporated under reduced pressure, at 90 DEG C, react 4h, decompression steams 900mL n-butyl acetate, stirred crystallization at 5 DEG C, and filter and the dry dry product 228g obtaining formula 3 compound, yield is 83%; As shown in Figure 1, ESI-MS (m/z): 483 [M+H]
+, 505 [M+Na]
+, 521 [M+K]
+;
(2) under room temperature, 100g formula 3 compound, 150mL methylene dichloride, 500mL dehydrated alcohol are added in the there-necked flask of 1000mL successively, be stirred to dissolution of solid, control temperature adds sodium amide 5 ~ 10g under 0 ~ 10 DEG C of state, is then slowly warming up to 20 ~ 25 DEG C of reactions and disappears to TLC monitoring reaction Chinese style 3 compound;
Methylene dichloride is removed in decompression, and controlling bath temperature is 20 ~ 25 DEG C, reduces pressure again and remove 10min when temperature is consistent with bath temperature in there-necked flask; In there-necked flask, add 100mL dehydrated alcohol and stir, control temperature is below 10 DEG C, and the sal volatile with 40% regulates reaction solution pH to 9 ~ 10; Be warming up to 25 DEG C of reaction 4h, adding 1200mL water after reaction terminates makes solid all dissolve, continue to be stirred to solid to separate out, then be cooled to 2 DEG C and stir 2h, to filter and by the ethanol of gained solid with 0 DEG C: water=1: mixed solvent 100mL × 2 of 3 are washed, and obtain off-white color solid 200g, air blast 40 DEG C of dry 12h, obtain formula 2 compound 107g, yield is 90%; As shown in Figure 2, ESI-MS (m/z): 500 [M+H]
+, 522 [M+Na]
+, 538 [M+K]
+;
(3), under room temperature, by 0.4moL n-hexyl alcohol, 0.4moL N-methylmorpholine, the mixing of 200mL methylene dichloride, reaction system is made to be cooled to 0 DEG C; In reaction system, add 0.3moL p-nitrophenyl chloroformate ester in 10 DEG C below in batches, after stirring reaction 1h, reaction mixture is used successively the HCl of 1mol/L, saturated NaHCO
3solution washing, concentrating under reduced pressure after washing, then add isopropyl ether crystallization, filtration drying obtains Powdered formula 7 compound 57.7g, and yield is 72%;
(4), under room temperature, 100g formula 2 compound, 1500mL acetone and 1000mL water are mixed, and adds 77g salt of wormwood stirring and dissolving; Reaction system is cooled to 0 ~-5 DEG C, drips the mixing solutions be made up of 300mL acetone and 70g formula 7 compound, stirring reaction 3h at 0 DEG C, then room temperature reaction 16h, less than 30 DEG C are evaporated to crude product and separate out, and filtration drying obtains formula 1 crude compound;
(5) added in 900mL acetonitrile by formula 1 crude compound, be heated to 55 ~ 70 DEG C of insulation 10min, elimination insolubles, is cooled to crystallizing at room temperature while hot, and filtration drying obtains Dabigatran compound solid 85g.As shown in Figure 3, ESI-MS (m/z): 628 [M+H]
+, molecular weight analyte 627 is consistent with target compound.
Embodiment 2:
In the present embodiment, the preparation method of dabigatran etcxilate comprises the following steps:
(1), under room temperature, by 50g formula 6 compound, the mixing of 400mL THF, 50mL triethylamine, be cooled to 0 DEG C, add 72mL tert-Butyl dicarbonate and insulation reaction 0.5h in less than 10 DEG C; Add 102g formula 4 compound after completion of the reaction, at 45 DEG C, react 2h; Add in 1000mL n-butyl acetate by organic layer evaporated under reduced pressure, at 90 DEG C, react 4h, decompression steams 400mL n-butyl acetate, stirred crystallization at 5 DEG C, and filter and the dry dry product 110g obtaining formula 3 compound, yield is 80%;
(2) under room temperature, 100g formula 3 compound, 150mL methylene dichloride, 500mL dehydrated alcohol are added in the there-necked flask of 1000mL successively, be stirred to dissolution of solid, control temperature adds sodium amide 5g under 0 ~ 10 DEG C of state, is then slowly warming up to 20 DEG C of reactions and disappears to TLC monitoring reaction Chinese style 3 compound;
Methylene dichloride is removed in decompression, and controlling bath temperature is 20 ~ 25 DEG C, reduces pressure again and remove 10min when temperature is consistent with bath temperature in there-necked flask; In there-necked flask, add 100mL dehydrated alcohol and stir, control temperature is below 10 DEG C, and the ammonium chloride solution with 40% regulates reaction solution pH to 9 ~ 10; Be warming up to 25 DEG C of reaction 5h, adding 1200mL water after reaction terminates makes solid all dissolve, continue to be stirred to solid to separate out, then be cooled to 2 DEG C and stir 2h, to filter and by the ethanol of gained solid with 0 DEG C: water=1: mixed solvent 100mL × 2 of 3 are washed, and obtain off-white color solid 200g, air blast 40 DEG C of dry 12h, obtain formula 2 compound 107g, yield is 90%;
(3), under room temperature, by 0.6moL n-hexyl alcohol, 0.6moL N-methylmorpholine, the mixing of 300mL methylene dichloride, reaction system is made to be cooled to 0 DEG C; In reaction system, add 0.45moL p-nitrophenyl chloroformate ester in 10 DEG C below in batches, after stirring reaction 1h, reaction mixture is used successively the HCl of 1mol/L, saturated NaHCO
3solution washing, concentrating under reduced pressure after washing, then add isopropyl ether crystallization, filtration drying obtains Powdered formula 7 compound 90g, and yield is 75%;
(4), under room temperature, 50g formula 2 compound, 1000mL acetone and 400mL water are mixed, and adds 39g salt of wormwood stirring and dissolving; Reaction system is cooled to 0 ~-5 DEG C, drips the mixing solutions be made up of 150mL acetone and 35g formula 7 compound, stirring reaction 3h at 0 DEG C, then room temperature reaction 16h, less than 30 DEG C are evaporated to crude product and separate out, and filtration drying obtains formula 1 crude compound;
(5) added in 400mL acetonitrile by formula 1 crude compound, be heated to 55 ~ 70 DEG C of insulation 10min, elimination insolubles, is cooled to crystallizing at room temperature while hot, and filtration drying obtains Dabigatran compound solid 45g.
Embodiment 3:
In the present embodiment, the preparation method of dabigatran etcxilate comprises the following steps:
(1), under room temperature, by 75g formula 6 compound, the mixing of 1000mL THF, 100mL triethylamine, be cooled to 0 DEG C, add 70mL pivaloyl chloride and insulation reaction 0.5h in less than 10 DEG C; Add 155g formula 4 compound after completion of the reaction, at 45 DEG C, react 2h; Add in 1500mL n-butyl acetate by organic layer evaporated under reduced pressure, at 90 DEG C, react 4h, decompression steams 700mL butylacetate, stirred crystallization at 5 DEG C, and filter and the dry dry product 175g obtaining formula 3 compound, yield is 85%;
(2) under room temperature, 100g formula 3 compound, 150mL methylene dichloride, 500mL dehydrated alcohol are added in the there-necked flask of 1000mL successively, be stirred to dissolution of solid, control temperature adds sodium amide 10g under 0 ~ 10 DEG C of state, is then slowly warming up to 25 DEG C of reactions and disappears to TLC monitoring reaction Chinese style 3 compound;
Methylene dichloride is removed in decompression, and controlling bath temperature is 20 ~ 25 DEG C, reduces pressure again and remove 10min when temperature is consistent with bath temperature in there-necked flask; In there-necked flask, add 100mL dehydrated alcohol and stir, control temperature is below 10 DEG C, and the sal volatile with 40% regulates reaction solution pH to 9 ~ 10; Be warming up to 25 DEG C of reaction 4h, adding 1200mL water after reaction terminates makes solid all dissolve, continue to be stirred to solid to separate out, then be cooled to 2 DEG C and stir 2h, to filter and by the ethanol of gained solid with 0 DEG C: water=1: mixed solvent 100mL × 2 of 3 are washed, and obtain off-white color solid 200g, air blast 35 DEG C of dry 12h, obtain formula 2 compound 107g, yield is 90%;
(3), under room temperature, by 0.4moL n-hexyl alcohol, 0.4moL N-methylmorpholine, the mixing of 200mL methylene dichloride, reaction system is made to be cooled to 0 DEG C; In reaction system, add 0.3moL p-nitrophenyl chloroformate ester in 10 DEG C below in batches, after stirring reaction 1h, reaction mixture is used successively the HCl of 1mol/L, saturated NaHCO
3solution washing, concentrating under reduced pressure after washing, then add isopropyl ether crystallization, filtration drying obtains Powdered formula 7 compound 57.7g, and yield is 72%;
(4), under room temperature, 40g formula 2 compound, 500mL acetone and 1000mL water are mixed, and adds 30g salt of wormwood stirring and dissolving; Reaction system is cooled to 0 ~-5 DEG C, drips the mixing solutions be made up of 100mL acetone and 30g formula 7 compound, stirring reaction 3h at 0 DEG C, then room temperature reaction 16h, less than 30 DEG C are evaporated to crude product and separate out, and filtration drying obtains formula 1 crude compound;
(5) added in 400mL acetonitrile by formula 1 crude compound, be heated to 55 ~ 70 DEG C of insulation 10min, elimination insolubles, is cooled to crystallizing at room temperature while hot, and filtration drying obtains Dabigatran compound solid 35g.
Claims (9)
1. a preparation method for dabigatran etcxilate, is characterized in that comprising the following steps:
(1) make following formula 6 compound and containing oxygen derivative react and generate following formula 5 compound, formula 5 compound reacts with following formula 4 compound and generates acid amides, underpressure distillation is except to be dissolved in by resistates after desolventizing in organic solvent and to react 3 ~ 5h at 75 ~ 95 DEG C, wash after completion of the reaction and concentrate organic phase, filtration, drying obtain following formula 3 compound;
Wherein, X is carbon or sulphur, and Y is the alkyl or the alkoxyl group that contain 1 ~ 10 carbon atom;
(2) formula 3 compound and sodium amide is made to be obtained by reacting following formula 2 compound;
(3) be dissolved in solvent by following formula 2 compound, and at 0 ~-5 DEG C, instill the reaction of following formula 7 compound, obtain following formula 1 compound after completion of the reaction, formula 1 compound is described Dabigatran compound.
2. the preparation method of dabigatran etcxilate according to claim 1, is characterized in that: formula 3 compound described in step (2) and sodium amide react in the mixed solvent of ethanol and methylene dichloride, and temperature of reaction is 20 ~ 25 DEG C.
3. the preparation method of dabigatran etcxilate according to claim 2, it is characterized in that: formula 3 compound and sodium amide described in step (2) react after solvent is removed in complete underpressure distillation and add in ammonium salt aqueous solution, at 0 ~ 10 DEG C, filtration after stirring 2 ~ 3h, drying, obtain described formula 2 compound.
4. the preparation method of dabigatran etcxilate according to claim 1, is characterized in that: described in step (1), the mol ratio of formula 6 compound and formula 4 compound is 1 ~ 2: 1.
5. the preparation method of dabigatran etcxilate according to claim 1, is characterized in that: described in step (3), the mol ratio of formula 2 compound and formula 7 compound is 1 ~ 2: 1.
6. the preparation method of dabigatran etcxilate according to claim 1, is characterized in that: the solvent described in step (3) is the mixed solution of acetone and water, and the volume ratio of described acetone and water is 0.5 ~ 2: 1.
7. the preparation method of dabigatran etcxilate according to claim 1, is characterized in that: the containing oxygen derivative described in step (1) is the one in acyl chlorides, acid anhydrides, tert-Butyl dicarbonate, chloro-formic ester.
8. the preparation method of dabigatran etcxilate according to claim 1, it is characterized in that: the organic solvent described in step (1) be in tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, acetonitrile, methylene dichloride, trichloromethane, ethyl acetate, isopropyl acetate, butylacetate any one or multiple.
9. the preparation method of dabigatran etcxilate according to claim 3, is characterized in that: described ammonium salt is volatile salt or ammonium chloride.
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| CN116239572A (en) * | 2023-02-28 | 2023-06-09 | 宿迁盛基医药科技有限公司 | Preparation method of dabigatran etexilate intermediate |
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| CN104987323B (en) | 2017-08-22 |
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